This application claims priority under 35 U.S.C. xc2xa7119 from GB Application No. 0108973.9, filed Apr. 10, 2001.
This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are spiroether derivatives of 1-phenyl-8-azabicyclo[3.2.1]octane, which are useful as neurokinin 1 (NK-1) receptor antagonists.
The present invention provides compounds of the formula (I): 
wherein
Z is xe2x80x94CR9R10CH2xe2x80x94 or xe2x80x94CH2CR9R10xe2x80x94;
R1 represents hydrogen, hydroxy, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, C1-6alkoxy, fluoroC1-6alkoxy, hydroxyC1-6alkyl, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, phenoxy, benzyloxy, cyano, halogen, NRaRb, SRa, SORa, SO2Ra, OSO2Ra, NRaCOR12, CORa, CO2Ra or CONRaRb where Ra and Rb each independently represent hydrogen, C1-4alkyl or fluoroC1-4alkyl;
R2 represents hydrogen, halogen, C1-6alkyl or C1-6alkoxy;
or when R2 is adjacent to R1, they may be joined together such that there is formed a 5- or 6-membered saturated or unsaturated ring containing one or two atoms selected from nitrogen, oxygen, sulphur, NH or NRc, which ring is optionally substituted by one, two or three groups selected from hydroxy, C1-4alkyl, C1-3alkoxyC1-3alkyl, fluoroC1-4alkyl, phenyl, xe2x95x90O or xe2x95x90S, where Rc is C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, fluoroC1-4alkyl, phenyl or benzyl;
R3 represents hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, cyano, SRa, SORa, SO2Ra, NRaRb, NRaCOR12, CORa, CO2Ra, CONRaRb or C1-4alkyl substituted by cyano, CO2Ra or CONRaRb where Ra and Rb are as previously defined;
or R3 represents a 5- or 6-membered aromatic heterocyclic group containing 1, 2, 3 or 4 heteroatoms, selected from nitrogen, oxygen and sulphur, which group is optionally substituted by one or two groups selected from C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, trifluoromethyl, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, phenyl, xe2x80x94(CH2)rNRaRb, xe2x80x94(CH2)rNRaCORb, xe2x80x94(CH2)rCONRaRb, or CH2C(O)Ra, where Ra and Rb are as previously defined and r is zero, 1 or 2;
R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1-6alkyl, CF3 or C1-6alkoxy substituted by C1-4alkoxy;
R6 represents hydrogen, hydroxy, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl optionally substituted by a group selected from (CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR14, CONR11C2-6alkenyl, CONR11C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl);
or R6 represents a group of the formula xe2x80x94CH2Cxe2x89xa1CCH2NR7R8 where R7 and R8 are as defined below;
or R6 represents C1-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by xe2x95x90O or xe2x95x90S and optionally substituted by a group of the formula xe2x80x94Yxe2x80x94NR7R8 where
Y is C1-6alkylene or C3-6cycloalkyl;
R7 represents hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 represents hydrogen or C1-4alkyl, C1-4alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by a group selected from C1-4alkoxy, hydroxyl, CO2Ra, NRaRb, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, phenyl, benzyl or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is as previously defined;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Y, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 represents hydrogen, hydroxy, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, hydroxyC1-6alkyl, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, aryl, aryl(CH2), aryloxy, aryl(CH2)oxy, cyano, halogen, NR7R8, CH2NR7R8, SR12, SOR12, SO2R12, OSO2R12, NRaCOR12, CH(OH)R12, COR12, CO2R12, CONR7R8, CH2OR13, heteroaryl or heteroarylC1-4alkyl, wherein Ra is as previously defined;
R10 represents hydrogen, halogen or hydroxy;
R11 represents hydrogen or C1-6alkyl;
R12 represents hydrogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl;
R13 represents C1-4alkyl substituted by a group selected from hydroxy, CORa, CO2Ra, CONRaRb and heteroaryl, where Ra is as previously defined;
R14 represents ORa, CONRaRb or heteroaryl;
and pharmaceutically acceptable salts or N-oxides thereof.
A preferred class of compound of formula (I) is that wherein R1 is a C1-6alkoxy, fluoroC1-6alkoxy or C3-7cycloalkoxy group, or R1 together with the group R2 forms a 5-membered saturated ring containing one oxygen atom, which ring is optionally substituted by a methyl group.
A particularly preferred class of compound of formula (I) is that wherein R1 is methoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, cyclopropoxy or R1 together with the group R2 represents xe2x80x94OCH(CH3)CH2xe2x80x94 or xe2x80x94N(CH3)C(O)C(CH3)2xe2x80x94 to complete a 5-membered saturated ring, or xe2x80x94CH(OH)CH2OC(CH3)(CF3)xe2x80x94, xe2x80x94CH2CH2C(O)N(CH3)xe2x80x94 or xe2x80x94CH(OH)CH2C(O)N(CH3)xe2x80x94 to complete a 6-membered saturated ring. Most especially, R1 is methoxy or cyclopropoxy.
Another preferred class of compound of formula (I) is that wherein R2 is a hydrogen, fluorine or chlorine atom, especially a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R3 is a hydrogen or halogen atom or a fluoroC1-6alkoxy group, especially fluorine, trifluoromethoxy or 2,2,2-trifluoroethoxy, or a 5-membered aromatic heterocyclic group as previously defined. Most preferably, R3 is trifluoromethoxy or 5-(trifluoromethyl)tetrazol-1-yl, and especially trifluoromethoxy.
A particularly preferred class of compound of formula (I) is that wherein R1 is attached at the 2-position of the phenyl ring and R3 is attached at the 5-position of the phenyl ring.
A further preferred class of compound of formula (I) is that wherein R4 is a hydrogen atom or a fluorine atom.
Another preferred class of compound of formula (I) is that in which R5 is a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R6 is a hydrogen atom or a C1-6alkyl group. Most especially, R6 is hydrogen or methyl.
Also preferred is the class of compound of formula (I) in which R6 is a C1-6alkyl group, in particular CH2, CH(CH3) and CH2CH2 and especially CH2, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined.
In particular, the 5-membered ring is a heterocyclic ring selected from 1,3-imidazol-4-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, 2-oxo-1,3-imidazol-4-yl, and 3-oxo-1,2,4-triazol-5-yl, any of which rings being optionally substituted by the group xe2x80x94Yxe2x80x94NR7R8.
Particularly preferred heterocyclic rings are selected from: 
Another preferred class of compound of formula (I) is that wherein R9 represents hydrogen, hydroxy, oxo, C1-6alkoxy, C1-6alkoxyC1-4alkyl, hydroxyC1-4alkyl, cyano, NR7R8, CH2NR7R8, SO2Rd, CH(OH)R12, COR12, CO2R12, CONR7R8, phenyl, heteroaryl, heteroarylC1-4alkyl or CH2OR13, where said phenyl is optionally substituted by one or two substituents selected from C1-4alkyl, C1-4alkoxy, halogen or trifluoromethyl.
A further preferred class of compound of formula (I) is that wherein R9 represents hydrogen, SO2Rd (in particular where Rd is phenyl) or CONR7R8 (in particular where R7 is C1-4alkyl or C2-4alkyl substituted by a hydroxyl or C1-2alkoxy group and R8 is hydrogen, C1-4alkyl, C1-4alkoxy or C2-4alkyl substituted by a hyxdroxyl or C1-2alkoxy group, or R7 and R8, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C1-4alkyl, hydroxyC1-2alkyl, C1-4alkoxyC1-2alkyl, phenyl or benzyl group).
Another preferred class of compound of formula (I) is that wherein R10 represents hydrogen, fluorine or hydroxy, and in particular that wherein R10 is hydrogen.
Certain particularly apt compounds of the present invention include those wherein R3 is a group selected from pyrrole, furan, thiene, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyridine, pyrazole, imidazole, oxazole, isoxazole, pyrazine, pyrimidine, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
Particularly preferred compounds of the present invention are those wherein R3 is a group selected from furan, pyridine, pyrimidine, 1,2,3-triazole, 1,2,4-triazole and tetrazole, each heteroaryl group being optionally substituted as previously defined.
An especially preferred class of compound of formula (I) is that wherein R3 is the group 
where R15 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CORa, CO2Ra, (CH2)rCONRaRb, (CH2)rNRaRb or (CH2)rNRaCORb, where Ra and Rb are hydrogen or C1-4alkyl, and r is zero, 1 or 2.
The optionally substituted tetrazolyl group is particularly preferred.
R15 is preferably hydrogen, C1-4alkyl, especially methyl, CF3, (CH2)rCONRaRb, SORa or SO2Ra where Ra, Rb and r are as previously defined. Most especially, R15 is CF3.
One favoured group of compounds of the present invention is of the formula (Ia) and pharmaceutically acceptable salts thereof: 
wherein R1, R2, R3 and R4 are as defined in relation to formula (I) and Z is xe2x80x94CR9R10CH2xe2x80x94.
With respect to compounds of the formula (I), Y (where present), may be a linear, branched or cyclic group. Favourably Y contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A particularly favourable group Y is CH2.
With respect to compounds of the formula (I), R7 may aptly be a C1-4alkyl group or a C2-6alkyl group substituted by a hydroxyl or C1-2alkoxy group, R8 may aptly be hydrogen or a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or C1-2alkoxy group, or R7 and R8 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a C1-4alkyl group or a C2-4alkyl group substituted by a hydroxy or C1-2alkoxy group.
Where the group NR7R8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR7R8 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where R8 represents a C2-4alkyl group substituted by a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, suitable rings include azetidinyl, pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings.
Particularly suitable moieties xe2x80x94Yxe2x80x94NR7R8 include those wherein Y is CH2 or CH2CH2 and NR7R8 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.
In particular, Y is preferably CH2 and NR7R8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
It will be appreciated that, where R9 represents an oxo (xe2x95x90O) group, then R10 will be absent and the group Z will in fact represent xe2x80x94C(O)CH2xe2x80x94 or xe2x80x94CH2C(O)xe2x80x94.
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms xe2x80x9cfluoroC1-6alkylxe2x80x9d and fluoroC1-6alkoxyxe2x80x9d mean a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term xe2x80x9cfluoroC1-4alkylxe2x80x9d means a C1-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
As used herein, the term xe2x80x9chydroxyC1-6alkylxe2x80x9d means a C1-6alkyl group, in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by a hydroxy group. Preferred are hydroxyC1-3alkyl groups, especially where one hydrogen atom has been replaced by a hydroxy group, for example, CH2OH, CH2CH2OH and C(CH3)2OH.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
As used herein, the term xe2x80x9carylxe2x80x9d as a group or part of a group means a monocyclic, fused-bicyclic or linear bicyclic aromatic ring containing 6, 10 or 12 carbon atoms, any of which rings is optionally substituted by one, two or three substituents selected from halogen, C1-6alkyl, C1-6alkoxy, or trifluoromethyl. Particular examples of such groups include phenyl, naphthyl and biphenyl. Phenyl is especially preferred.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d as a group or part of a group means a monocyclic or fused-bicyclic heteroaromatic ring containing between 5 and 10 ring members, of which 1 to 4 may be heteroatoms selected from N, O and S, and wherein any of which rings is optionally substituted by one or two substituents selected from halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl or phenyl. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indole, benzofuran, benzthiophene, benzimidazole, benzoxazole and benzthiazole. Furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, and pyridyl are particularly preferred. Where said rings are substituted, preferred substituents include methyl and phenyl groups.
When used herein the term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
Specific compounds within the scope of this invention include:
(1R*,2R*,4xe2x80x2S*,5S*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-methoxy-5-trifluoromethoxyphenyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5S*,6R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-methoxy-5-trifluoromethoxyphenyl)-1-phenyl-6-phenylsulphonylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5S*)-4xe2x80x2-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-isopropoxy-5-trifluoromethoxyphenyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-(2xe2x80x2,2xe2x80x2-difluoro)ethoxy-5-trifluoromethoxyphenyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-1-phenyl-4xe2x80x2-[2-(2,2,2-trifluoroethoxy)-5-trifluoromethoxyphenyl)spiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-4xe2x80x2-[2-(2-Fluoroethoxy)-5-trifluoromethoxyphenyl]-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5S*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-[(2RS)-2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran-7-yl]-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-methoxy-5-trifluoromethoxyphenyl)-6-(morpholin-1-ylcarbonyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-methoxy-5-trifluoromethoxyphenyl)-6-(3-methoxypropylaminocarbonyl)-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan];
(1R*,2R*,4xe2x80x2S*,5R*)-2xe2x80x2,3xe2x80x2,4xe2x80x2,5xe2x80x2-tetrahydro-4xe2x80x2-(2-methoxy-5-trifluoromethoxyphenyl)-6-(3-methoxypropylaminocarbonyl)-8-methyl-1-phenylspiro[8-azabicyclo[3.2.1]octane-2,2xe2x80x2-furan]; and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the xe2x80x9cparent drugxe2x80x9d or xe2x80x9cparent moleculexe2x80x9d) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of formula (I) and (Ia) will have the stereochemistry of the 1, 2, 4xe2x80x2 and 5 positions as possessed by, for instance, the compound of Example 11, i.e. as shown in formula (Ib) 
It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred class of compound represented by formula (Ia) and formula (Ib).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in U.S. Pat. No. 6,071,927, the content of which is incorporated herein by reference (see in particular, column 8, line 50 to column 10, line 4).
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. A comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in U.S. Pat. No. 6,071,927, the content of which is incorporated herein by reference (see, in particular, column 10, line 14 to column 22, line 18).
In particular, the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
The compounds of the present invention are also particularly useful in the treatment of nociception and pain. Diseases and conditions in which pain predominates, include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.
The compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.
The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn""s disease and irritable bowel syndrome.
The compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
As used herein, the term xe2x80x9ctreatmentxe2x80x9d includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
According to a general process (A), compounds of formula (I) may be prepared by the reaction of a compound of formula (II) 
and a compound of formula (III) 
where Hal is chlorine, bromine or, preferably, iodine, by a reductive Heck reaction using a palladium catalyst such as palladium acetate with, for example, tri-o-tolylphosphine, dimethylformamide and tributylamine, or tetrabutylammonium chloride and dimethylformamide, and a reducing agent, preferably formic acid or a salt thereof, such as potassium formate.
According to another general process (B), compounds of formula (I) may be prepared by the reaction of a compound of formula (IV) 
wherein each R45 is a C1-4alkyl group, preferably methyl or n-butyl groups, with a compound of formula (V) 
wherein R50 is a leaving group such as triflate (xe2x80x94OSO2CF3) or a halogen atom, for example, chlorine, bromine or iodine, especially triflate, bromine or iodine.
The reaction is conveniently effected in the presence of lithium chloride and a transition metal catalyst such as triphenylphosphine palladium (0). Suitable solvents for the reaction include an aromatic hydrocarbons, for example, toluene, polar aprotic solvents, for example, dimethylformamide, or ethers, for example, dioxan, the reaction being effected at a temperature between 80xc2x0 C. and the reflux temperature of the solvent. Subsequent reduction of the double bond is effected using the conditions of general process (G), below.
According to another general process (C), compounds of formula (I) may be prepared by the reduction of a compound of formula (VI) 
using, for example, a borohydride such as lithium borohydride or lithium triethylborohydride in tetrahydrofuran, or a hydride such as lithium aluminium hydride or diisobutylaluminium hydride.
According to another general process (D), compounds of formula (I) wherein R1 is C1-6alkoxy, fluoroC1-6alkoxy, C2-6alkenoxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy or benzyloxy, may be prepared by the interconversion of a compound of formula (I) wherein R1 is hydroxy, hereinafter referred to as formula (VII) 
by reaction with an appropriate alkyl-, fluoroalkyl-, alkenyl-, cycloalkyl-, cycloalkylalkyl- or aralkyl-halide, especially the iodide, in the presence of a base.
Suitable bases include alkali metal hydrides, such as sodium hydride, in a suitable solvent such as dimethylformamide. The reaction is conveniently effected at about room temperature.
According to another general process (E), compounds of formula (I) may be prepared by the interconversion of a corresponding compound of formula (I) in which R6 is H, hereinafter referred to as formula (VIII) 
by reaction with a compound of formula (IX):
LGxe2x80x94R6axe2x80x83xe2x80x83(IX)
where R6a is a group of the formula R6 as defined in relation to formula (I) (other than H) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R6a is a precursor group, converting it to a group R6 (in which process any reactive group may be protected and thereafter deprotected if desired).
This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
Suitable alternative methods for introducing the group R6 are described, for instance, in International Patent Specification No. WO 95/18124.
According to another general process (F), compounds of formula (I) may be prepared from a compound of formula (X) 
by either
(a) reaction with lithium naphthalenide in tetrahydrofuran, the reaction being effected at reduced temperature, for example at about xe2x88x9278xc2x0 C.; or
(b) in a first step, oxidation of the phenylthio moiety using, for example, oxone in the presence of aluminium oxide, the reaction being effected in a suitable solvent such as a halogenated hydrocarbon, for example, chloroform, and conveniently at room temperature, and in a second step, removal of the phenylsulfonyl moiety using, for example, sodium amalgam in the presence of disodium hydrogen orthophosphate, the reaction being effected in a suitable solvent such as an alcohol, for example, methanol, and at a reduced temperature, for example, between 0xc2x0 C. and 10xc2x0 C.
According to another general process (G), compounds of formula (I) may be prepared by the reduction of a compound of formula (XI) 
wherein the dotted line represents a double bond at either bond (a) or bond (b).
Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (II) may prepared, for example, by the conversion of a stannane of formula (IV) to the corresponding iodide by treatment with iodine at reduced temperature, for example, at about xe2x88x9278xc2x0 C., in a suitable solvent such as dichloromethane. The iodine may then be displaced to give the compound of formula (II) by treatment with, for example, xcex1,xcex1xe2x80x2-azo-isobutyronitrile and tributyltin hydride in a suitable solvent, for example, toluene, at an elevated temperature, for example, at about 100xc2x0 C.
Alternatively, compounds of formula (II) may be prepared by the cyclization of a compound of formula (XII) 
using triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran.
Compounds of formula (XII) may be prepared by the partial reduction of an acetylene compound of formula (XIII) 
The reaction is conveniently effected by catalytic hydrogenation using a metal catalyst such as palladium on calcium carbonate in the presence of a lead poison (e.g. Lindlar catalyst). Other suitable methods will be readily apparent to a person of ordinary skill in the art.
Compounds of formula (XIII) may be prepared from compounds of formula (XIV) 
and, for example, a Grignard reagent prepared from O-trimethylsilylpropargyl alcohol using conventional methodology, followed by removal of the hydroxy protecting group.
Compounds of formula (IV) may be prepared from a compound of formula (XIII) by reaction with a compound of the formula (R45)3SnH, for example tri-(n-butyl)stannane in the presence of a transition metal catalyst such as tetrakis(triphenylphosphine)palladium(0) in a suitable solvent such as an ether, for example, tetrahydrofuran, followed by a dehydration step using, for example, triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as an ether, for example, tetrahydrofuran.
Alternatively, compounds of formula (IV) may be prepared from a compound of formula (XV) 
wherein R50 is as previously defined (and is preferably a triflate group or a bromine or iodine atom), by reaction with a compound of the formula (R45)3Snxe2x80x94Sn(R45)3, for example, hexamethyl distannane. The reaction is conveniently effected in the presence of a base, for example, lithium carbonate, and a catalyst such as triphenylphosphine palladium(0). Suitable solvents for the reaction include ethers such as tetrahydrofuran, the reaction being effected at a temperature between room temperature and 100xc2x0 C., for example, at about 60xc2x0 C.
Compounds of formula (XV) may be prepared from a compound of formula (XX) by enolisation of the ketone in the presence of a base, for example, sodium hexamethyldisilazide, followed by reaction with a reagent capable of introducing a suitable leaving group, for instance, where R50 is xe2x80x94OSO2CF3, using 2-[N,N-bis(trifluoromethylsulphonyl)amino]-5-chloropyridine or triflic anhydride. The reaction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran at a reduced temperature, for instance, xe2x88x9280xc2x0 C.
Compounds of formula (VI) may be prepared by reduction of a compound of formula (XVI) 
Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.
Compounds of formula (XVI) may be prepared from a compound of formula (XVII) 
by a three-step process. Fierily, the compound of formula (XVII) is reduced using, for example, Red-Al(trademark) in a suitable aprotic solvent such as an aromatic hydrocarbon, for example, toluene, or an ether, for example, diethyl ether, or a mixture thereof. The resultant compound is then iodinated using iodine. Finally cyclisation takes place by reaction with carbon monoxide in the presence of a transition metal catalyst such as tris(dibenzylidineacetone)palladium(0) and 1,4-bis(diphenylphosphino)butane, and an organic base such as a trialkylamine, for example, isopropyldiethylamine. The cyclisation is conveniently effected in an aprotic solvent such as an ether, for example, tetrahydrofuran.
Compounds of formula (XVII) may be prepared by the reaction of a compound of formula (XIV) with a compound of formula (XVIII) 
The reaction is conveniently effected in the presence of ethyl magnesium bromide in a suitable aprotic solvent such as an ether, for example, tetrahydrofuran.
Compounds of formula (X) may be prepared from a compound of formula (VII) by reaction with (1-iodo-cycloprop-1-yl)phenylsulfide.
Compounds of formula (XI) may be prepared by the dehydration of a compound of formula (XIX) 
using an acid such as trifluoroacetic acid. The reaction is conveniently effected at a temperature between 0xc2x0 C. and room temperature, using a suitable organic solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formula (XIX) may be prepared by the reaction of a compound of formula (XX) 
with a Grignard reagent prepared from a compound of formula (III), preferably using magnesium and a bromide of formula (III). The coupling reaction is conveniently effected at reduced temperature, for example, at about 0xc2x0 C., using a suitable solvent such as an ether, for example, diethyl ether.
Compounds of formula (XX) may be prepared from a compound of formula (XIV) by a variety of processes, for instance, by the following reaction sequence (Scheme A) or by methods analogous thereto: 
Compounds of formula (XIV) may be prepared from a compound of formula (XXI) 
by catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, for example, methanol or ethanol, or an ester, for example, ethyl acetate, or an organic acid, for example, acetic acid, or a mixture thereof.
Compounds of formula (XI) wherein R6 is benzyl or allyl, may be prepared from a compound of formula (XXII) 
(or a corresponding compound wherein the Oxe2x88x92 is OH, and the compound is associated with a counterion, such as a bromide or chloride ion) by reaction with a vinyl compound of the formula R9CHxe2x95x90CH2, in particular where R9 is cyano, SO2R13 (especially where R13 is phenyl) or CO2R13 (especially where R13 is tert-butyl), in the presence of an organic base such as a trialkylamine, for example, triethylamine. The reaction is conveniently effected in an aprotic solvent such as an aromatic hydrocarbon, for example, toluene.
The reaction of a compound of formula (XXII) with acrylonitrile is particularly suitable for preparing compounds where the R9 substituent is situated on either of the carbon atoms of the two-carbon bridge.
Where they are not commercially available, the intermediates of formula (II), (IV) and (XVIII) above may be prepared, for example, from the corresponding phenol derivative using, for example, the procedures described in the accompanying Examples, or by alternative procedures which will be readily apparent to one skilled in the art.
In a preferred embodiment of the aforementioned processes, R6 is a benzyl group. The various reduction reactions described above may conveniently replace the benzyl group with a hydrogen atom. It will be appreciated from the discussion above that compounds of formula (I) wherein R6 is a hydrogen atom are particularly preferred precursors to other compounds of formula (I).
Compounds of formula (IX) and (XXII) are either known compounds or may be prepared by methods analogous to those described herein.
It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC50 at the human NK1 receptor of less than 100 nM on said test method.